Oral infectious diseases remain major challenges in modern Dentistry. Caries and periodontal diseases are considered to be the most prevalent diseases in the industrialized world. The major oral infectious diseases are caused by opportunistic pathogens, and Philip Marsh has reviewed (Microbiology 149:279-294, 2003) the basis for considering Dental infectious diseases as prime examples of ecological catastrophes. Disease occurs as a result of shifts, due to stress conditions, in oral biofilm communities;thereby, favoring organisms that possess so-called pathogenic personalities. For example, highly aciduric organisms or those with high capacities to induce inflammatory responses of the host might thrive under these conditions. The development of new types of antimicrobials, other than antibiotics, is currently perhaps the most promising approach for preventing and treating oral infectious diseases. We have shown that the formation of mono- unsaturated membrane fatty acids (UFAs) is important for the ability of S. mutans to survive acidic environments (Fozo and Quivey, 2004a and b). Further, we have shown that the formation of unsaturated fatty acids in S. mutans is dependent on a single enzyme, FabM (Fozo and Quivey, 2004b). We include more recent data in the Preliminary Studies section to show that loss of FabM dramatically lowers the ability of S. mutans to cause disease in rats. The FabM enzyme is presently identified in only 3 bacterial genera: the Streptococci. Staphylococci, and Fusobacteria. Thus, knowledge about the role of the enzyme in S. mutans will shed light on other important human pathogens. Nevertheless, we are currently lacking information regarding the regulation of membrane biosynthesis enzymes, and how those enzymes are used by S. mutans to control membrane homeostasis. Our hypothesis is that S. mutans regulates its membrane composition in response to external acidification in order to maintain homeostasis in membrane fluidity. We propose a series of experiments designed to complete our earlier work and to test our hypothesis. [Our goal is to achieve a thorough understanding of the S. mutans membrane biosynthesis during growth at low pH. Our Specific Aims are as follows: 1) we will complete our biochemical characterization of pH-dependent changes in membranes, with the goal of measuring changes in phospholipids and branched chain fatty acids;2) we will use biochemical and molecular tools to determine the mechanism of genetic regulation of fab genes and the role of fabR in regulating the fab gene cluster;3) we will use biochemical and genetic tools to elucidate the relationship of FabM and FabK to membrane composition;4) we will determine how pH-dependent changes in S. mutans membranes relate to fluidity;5) finally, we will determine how S. mutans uses its fab genes to respond to membrane disrupting agents such as cerulenin and tt-farnesol.